1. Field of Invention
This invention relates to a carrier base material to be combined with a therapeutically active medicament and formed into a solid, shaped dosage unit having a long-lasting and regular incremental release of the medicament upon administration. Specifically, this invention relates to a carrier base material, consisting essentially or predominantly of hydroxypropylmethylcellulose having a chemical structure and molecular weight which renders it suitable for use, in relatively low concentrations, in sustained release therapeutic compositions.
2. Description of the Prior Art
Hydroxypropylmethylcelluloses are commercially available in various grades, under several tradenames, including Methocel E, F, J and K (all previously designated as Methocel HG) from The Dow Chemical Co., U.S.A., HPM from British Celanese Ltd., England, and Metalose SH from Shin-Etsu, Ltd., Japan. The various grades available under a given tradename represent differences in methoxyl and hydroxypropoxyl content as well as molecular weight. The methoxyl content ranges from 16.5 to 30 weight-% and the hydroxypropoxyl content ranges from 4 to 32 weight-%, as determined by the method described in ASTM D-2363-72.
Commercial designations of the various hydroxypropylmethylcelluloses are based on the viscosities of 2% aqueous solutions at 20.degree. C. The viscosities range from 15 cps to 30,000 cps and represent number average molecular weights ranging from about 10,000 to over 150,000, as calculated from the data in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974).
A solid unit dosage form consisting of a mixture of a medicament and a carrier base material which is low molecular weight hydroxypropylmethylcellulose Methocel E50, formerly known as Methocel 60HG 50 cps, having a number average molecular weight of 23,000, a methoxyl content of 28-30 weight-% and a hydroxypropoxyl content of less than 9 weight-%, rapidly releases the medicament when brought into contact with the aqueous fluids of the mouth or the gastrointestinal tract. However, an effective "sustained release" tablet is produced by admixture of a medicament with a modified Methocel E50, per se or in admixture with other cellulose ethers. As disclosed by Lowey and Stafford (U.S. Pat. No. 3,870,790) and Schor (U.S. Pat. No. 4,226,849), the modification is carried out by exposure of the low molecular weight hydroxypropylmethylcellulose Methocel E50 to high humidity or moisture and drying in air.
In our co-pending application, Ser. No. 332,348 filed 12/18/81 it was disclosed that effective prolonged release therapeutic compositions may be prepared by using as a carrier base material a hydroxypropylmethylcellulose having a hydroxypropoxyl content of 9-12 weight-% and a number average molecular weight of less than 50,000, e.g. Metalose 60SH50. The carrier base material provides sustained release characteristics without treatment or modification.
Christenson and Huber (U.S. Pat. No. 3,590,117) reported that high viscosity grade, i.e. 15,000 cps, hydroxypropylmethylcellulose did not make an acceptable long-lasting troche because the troche would flake off in the mouth rather than dissolve uniformly.
Christenson and Dale (U.S. Pat. No. 3,065,143) disclosed the use of certain high molecular weight hydrophilic gums, including hydroxypropylmethylcelluloses, in the preparation of a "sustained release tablet". The tablet consisted essentially of a mixture of a medicament and at least one third part by weight of the weight of the tablet of a hydrophilic gum which rapidly absorbed water and swelled at 37.degree. C. to form a "soft mucilaginous gel barrier" on the surface of the tablet when brought into contact with the aqueous fluids of the gastrointestinal tract.
The high molecular weight hydroxypropylmethylcelluloses disclosed by Christenson and Dale and constituting at least one third of the weight of the tablet, include Methocel 60HG 4000 cps, now known as Methocel E4M, having a 28-30 weight-% methoxyl content, a 7.5-12 weight-% hydroxypropoxyl content and a number average molecular weight of 93,000, and Methocel 90HG 4000 cps and Methocel 90HG 15,000 cps, now known as Methocel K4M and Methocel K15M, respectively. The latter have number average molecular weights of 89,000 and 124,000, respectively, and a 19-24 weight-% methoxyl content, and a 4-12 weight-% hydroxypropoxyl content.
The present invention is directed toward further improvements in carrier base materials containing hydroxypropylmethylcelluloses for use in the preparation of sustained release solid pharmaceutical unit dosage forms, particularly with moisture sensitive and/or high dosage medicaments.